Background: Normal pressure hydrocephalus (NPH) has been an ongoing and challenging field of research for the past decades because two main issues are still not fully understood: the pathophysiologic mechanisms underlying ventricular enlargement and prediction of outcome after surgery. Purpose: To evaluate changes in diffusion tensor imaging (DTI) derived parameters in patients with suspected normal pressure hydrocephalus before and after withdrawal of cerebrospinal fluid (CSF). Material and Methods: Twenty-four consecutive patients with clinical and radiological suspicion of NPH and 14 agematched control subjects were examined with DTI on a clinical 3T scanner. Patients were examined before and 6–36 h after CSF drainage (interval between scans, 5 days). Fifteen patients were finally included in data analysis. Fractional anisotropy (FA) and mean, parallel, and radial diffusivity (MD, PD, RD) were evaluated using a combination of a ROI-based approach and a whole-brain voxel-by-voxel analysis. Results: Alteration of DTI parameters in patients with suspected NPH is regionally different. Compared to the control group, we found an elevation of FA in the subcortical white matter (SCWM) and corpus callosum, whereas the other diffusion parameters showed an increase throughout the brain in variable extent.We also found a slight normalization of RD in the SCWM in patients after lumbar drainage. Conclusion: Our results show that DWI parameters are regionally dependent and reflect multifactorial (patho-) physiological mechanisms, which need to be interpreted carefully. It seems that improvement of gait is caused by a decrease of interstitial water deposition in the SCWM.

<p>The manifestations of early sleep disturbances on cerebrospinal fluid and their relations with early developmental competencies are understudied. Recent studies highlight cerebrospinal fluid disbursement as a potential factor associated with dysfunctions in brain development. With two studies, we explored sleep and extra-axial cerebrospinal fluid (EA-CSF) connection as a potential mechanistic pathway by which sleep dysregulation influences brain and behavior development. Specifically, we evaluated associations between (1) EA-CSF to total cerebral volume (EA-CSF/TCV) ratios, (2) parent-report of child sleep problems, and (3) social communication development in typical (Study 1) and atypical populations (Study 2). In typical infants, early sleep problems did not precede later elevated EA-CSF/TCV ratios or social-communicative competence. Elevated EA-CSF/TCV ratios were associated with impaired social communication skills, suggesting that a relationship between elevated EA-CSF/TCV ratios and social communication impairments exists regardless of neurological or sleep problems. In an atypical population with autism spectrum disorder (ASD), older children with ASD had similar EA-CSF/TCV ratios to a group of their typically developing peers. Sleep problems were negatively associated with EA-CSF/TCV ratios but positively associated with social-communicative impairments for children with ASD, highlighting the influence of sleep problems on both brain and behavioral outcomes in an atypical population. In both studies, EA-CSF volumes continue to increase during early development in the typically developing populations (but not later in the atypical sample), underlining its relevance as a marker of atypical processing. Recognizing the potential roles of EA-CSF in influencing several biosocial and behavioral aspects of development, we encourage researchers to continue to explore EA-CSF growth, especially during developmental periods of flux and transition. Future work with longitudinal data can also serve to explore sleep-related developmental changes in EA-CSF, in association with behavioral and phenotypic changes. </p>

Huntingtons sjukdom (HD) är ett neurodegenerativt tillstånd som orsakas av mutationer i huntingtin gen (Htt), och resulterar till upprepade glutamin (polyQ) i Htt-proteinet. Muterad Htt kan inte vika sig ordentligt och börjar därför aggregera i celler. I detta projekt undersöktes molekylära mekanismerna bakom HD genom att analysera genuttryck hos musvävnader och jämföra detta med biomarkörer identifierats hos HD-patienter. För närvarande finns det ingen behandling för att stoppa utveckling av HD. Därför behövs det mer kunskap om sjukdomen. Projektets mål var att öka vår förståelse på regulatoriska mekanismer som ligger bakom den neurodegenerativa sjukdomen och identifiera potentiella diagnostiska biomarkörer. För denna studie användes mRNA-seq-data från 11 distinkta vävnader från Q175 HD-möss. Vävnader som analyserades inkluderar hjärnstammen, cerebellum, corpus callosum, hippocampus och thalamus/hypothalamus, fettvävnader (brun, vit nära gonad och vit nära tarm) och andra vävnader så som hjärta, hud och gastrocnemius muskel. Efter en grundlig genomgång av HD-litteraturen valdes biomarkörer som sedan undersöktes för mRNA-uttryck hos Q175-möss via Gene Set Enrichment Analysis (GSEA). Genuttrycksförändringar hos HD-möss visade sig vara vävnadsspecifika, med betydande effekter på hud och fettvävnader, men mindre effekter hos hjärnvävnader. Även om gemensamma mRNA-förändringar inte hittas bland de olika vävnader, uppvisade relaterade vävnader förändringar i samma pathways. Immunsvar och ribosomal dysfunktion var utbredd, men varje hjärnregion visade unika förändringar relaterade till sömn, synaptisk signalering och energiprocesser. Muskel- och fettvävnader uppvisar också distinkta mönstrar. Detta understryker vikten av vävnadsspecifik biomarkörforskning för neurodegenerativa sjukdomar. / Huntington's disease (HD) is a neurodegenerative condition caused by a mutation in the Huntingtin (Htt) gene which results in glutamine repeats (polyQ) and a longer Htt-protein. The mutated Htt-protein cannot fold properly and thus, is prone to aggregate in cells. There is currently no treatment available to stop the progression of HD. Therefore, there is a need for more knowledge regarding the disease. This project investigates the molecular mechanisms underlying HD by analysing gene expression program in wild type (Wt) and HD mice. The objective is to investigate changes in gene regulatory mechanisms underlying the neurodegenerative disease and identify potential diagnostic markers. For this study, mRNA-seq data from 11 distinct tissues from Q175 HD model mouse were analysed. These tissues included brainstem, cerebellum, corpus callosum, hippocampus, and thalamus/hypothalamus, adipose tissues (brown, white near gonad and white near intestine), heart, skin and gastrocnemius muscle. Following a thorough literature review, biomarkers of HD were chosen, and their expression investigated in the HD mouse using Gene Set Enrichment Analysis (GSEA). Gene expression changes in HD mouse were specific to different tissues, with significant changes identified in skin and adipose tissues, while smaller changes were detected in the brain tissues. While common changes across the 11 tissues were not found, related tissues exhibited alterations in the same pathways. Changes in immune response and ribosomal dysfunction were widespread across tissues. Moreover, each brain region showed unique changes related to sleep, synaptic signalling, and energy processes. Muscle and adipose tissues displayed distinctive patterns. These results underscore the importance of tissue-specific biomarker research for neurodegenerative diseases.

No / PURPOSE: To investigate cerebrospinal fluid (CSF) dynamics in the aqueduct of Sylvius (AoS) in chronic cerebrospinal venous insufficiency (CCSVI)-positive and -negative healthy individuals using cine phase contrast imaging. MATERIALS AND METHODS: Fifty-one healthy individuals (32 CCSVI-negative and 19 age-matched CCSVI-positive subjects) were examined using Doppler sonography (DS). Diagnosis of CCSVI was established if subjects fulfilled >/=2 venous hemodynamic criteria on DS. CSF flow and velocity measures were quantified using a semiautomated method and compared with clinical and routine 3T MRI outcomes. RESULTS: CCSVI was associated with increased CSF pulsatility in the AoS. Net positive CSF flow was 32% greater in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.008). This was accompanied by a 28% increase in the mean aqueductal characteristic signal (ie, the AoS cross-sectional area over the cardiac cycle) in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.021). CONCLUSION: CSF dynamics are altered in CCSVI-positive healthy individuals, as demonstrated by increased pulsatility. This is accompanied by enlargement of the AoS, suggesting that structural changes may be occurring in the brain parenchyma of CCSVI-positive healthy individuals.

Η Ηλεκτροεγκεφαλογραφία (ΗΕΓ) και η Μαγνητοεγκεφαλογραφία (ΜΕΓ) αποτελούν δύο από τις πλέον ευρέως χρησιμοποιούμενες μη επεμβατικές μεθόδους μελέτης της λειτουργίας του ανθρώπινου εγκεφάλου, κατά τις οποίες καταγράφονται εξωτερικά του κρανίου, το ηλεκτρικό και το μαγνητικό πεδίο, που οφείλονται στη διέργεση εγκεφαλικών νευρώνων. Oι κύριες βιοηλεκτρικές πηγές των πεδίων που καταγράφονται σ’ αυτά, είναι ομάδες νευρώνων, που προτυποποιούνται με ένα ηλεκτρικό δίπολο. Αρχικά επιλέγεται το πλέον ρεαλιστικό πρότυπο των τριών φλοιών. Δηλαδή ως αγωγός θεωρείται ολόκληρο το κρανίο, συμπεριλαμβανομένου του δέρματος, των κρανιακών οστών, του εγκεφαλονωτιαίου υγρού και του εγκεφαλικού ιστού – περιοχές διαφορετικής ηλεκτρικής αγωγιμότητας – και υπολογίζεται το ηλεκτρικό δυναμικό και το μαγνητικό πεδίο, επιλύεται δηλαδή τόσο το ευθύ πρόβλημα ΗΕΓ, όσο και το αντίστοιχο ΜΕΓ, στη σφαιρική και στην ελλειψοειδή γεωμετρία. Το δεύτερο πρότυπο αφορά στην επίλυση του ευθέος προβλήματος ΗΕΓ για την περίπτωση όπου ο εγκεφαλικός ιστός θεωρηθεί ως ένα σφαιρικός αγωγός, στο εσωτερικό του οποίου βρίσκεται είτε ομόκεντρα μια σφαιρική περιοχή υγρού, οπότε χρησιμοποιείται για την επίλυση το σφαιρικό σύστημα συντεταγμένων, είτε έκκεντρα, οπότε χρησιμοποιείται αντίστοιχα το δισφαιρικό. Τέλος, ως αγωγός θεωρείται μια ομογενής σφαίρα, περίπτωση όπου η ακριβής και πλήρης αναλυτική λύση για το πρόβλημα του Βιομαγνητισμού είναι γνωστή. Η συνεισφορά όμως της διατριβής για το πρότυπο αυτό είναι στη δημιουργία χρήσιμων εργαλείων για την μετατροπή των αναπτυγμάτων των λύσεων σε σειρές, στις αντίστοιχες κλειστές μορφές μέσω της άθροισης των σειρών, καθώς και στην εξαγωγή συμπερασμάτων σχετικά με το αντίστροφο πρόβλημα ΗΕΓ, τα οποία προκύπτουν από τη γραφική επεξεργασία της κλειστής λύσης του ηλεκτρικού δυναμικού, όπως αυτή προέκυψε από τη μέθοδο των ειδώλων. / Electroenchephalography (EEG) and Magnetoenchephalophy (MEG) are common non invansive methods for studying the function of the human brain. Considering that the data of the generated electric potential (Electroencephalogram) and the magnetic field (Magnetoenchephalogram), takes place on or in the surrounding the head, the entire head, including the skin, the bones, the cerebrospinal fluid and the cerebral, regions which are characterizing by different electric conductivity are including. For this model, the direct Bioelectromagnetism problem is solved in both spherical and ellipsoidal geometry. Specifically, the leading terms of the electric potential in the exterior of the conductor and everywhere in the interior, as well as the leading quadrupolic term of the multipole expansion of the exterior magnetic induction field in the ellipsoidal geometry, are obtained. The reduction of the the ellipsoidal results to the corresponding spherical case, which has brought up useful conclusions concerning these two geometrical models, is also presented. The direct EEG problem is described, for the case where the entire cerebral is considered as a spherical conductor, which surrounds a fluid spherical region of different conductivity. When the two spherical regions are concentric, the problem is solved with the spherical geometry, but when these are eccentric the problem is solved with the bispherical geometry. Finally, the exact and complete analytic solution for the forward EEG problem is produced by the Image Theory for the homogeneous spherical conductor and is elaborated graphically. In particular, some electric potential distributions are produced on the surface of the spherical brain, where the equipotential curves are represented by circles. Considering these distributions, a parametric analysis of the position and the orientation o the moment dipole is accomplished for the current dipole that has considered in this thesis. Consequently, when the source is near the surface, the orientation of the moment is directed vertically to the zero equipotential circle to the increase potential, since the position vector of the source tends to become vertical to the maximum equipotential curves. The existence of special position and orientation of the source, for which the contribution in the external magnetic field is zero - and for the spherical case, where the position and the orientation of the sources are parallel - corresponds to parallel equipotential curves.

Chronic pain affects 20 % of the global population, causes suffering, is difficult to treat, and constitutes a large economic burden for society. So far, the characterization of molecular mechanisms of chronic pain-like behaviors in animal models has not translated into effective treatments. In this thesis, consisting of five studies, pain patient biofluids were analyzed with modern proteomic methods to identify biomarker candidates that can be used to improve our understanding of the pathophysiology chronic pain and lead to more effective treatments. Paper I is a proof of concept study, where a multiplex solid phase-proximity ligation assay (SP-PLA) was applied to cerebrospinal fluid (CSF) for the first time. CSF reference protein levels and four biomarker candidates for ALS were presented. The investigated proteins were not altered by spinal cord stimulation (SCS) treatment for neuropathic pain. In Paper II, patient CSF was explored by dimethyl and label-free mass spectrometric (MS) proteomic methods. Twelve proteins, known for their roles in neuroprotection, nociceptive signaling, immune regulation, and synaptic plasticity, were identified to be associated with SCS treatment of neuropathic pain. In Paper III, proximity extension assay (PEA) was used to analyze levels of 92 proteins in serum from patients one year after painful disc herniation. Patients with residual pain had significantly higher serum levels of 41 inflammatory proteins. In Paper IV, levels of 55 proteins were analyzed by a 100-plex antibody suspension bead array (ASBA) in CSF samples from two neuropathic pain patient cohorts, one cohort of fibromyalgia patients and two control cohorts. CSF protein profiles consisting of levels of apolipoprotein C1, ectonucleotide pyrophosphatase/phosphodiesterase family member 2, angiotensinogen, prostaglandin-H2 D-isomerase, neurexin-1, superoxide dismutases 1 and 3 were found to be associated with neuropathic pain and fibromyalgia. In Paper V, higher CSF levels of five chemokines and LAPTGF-beta-1were detected in two patient cohorts with neuropathic pain compared with healthy controls. In conclusion, we demonstrate that combining MS proteomic and multiplex antibody-based methods for analysis of patient biofluid samples is a viable approach for discovery of biomarker candidates for the pathophysiology and treatment of chronic pain. Several biomarker candidates possibly reflecting systemic inflammation, lipid metabolism, and neuroinflammation in different pain conditions were identified for further investigation. / Uppsala Berzelii Technology Centre for Neurodiagnostics